WO 94/22856 discloses 14-hydroxy-taxanes having improved antitumor properties compared with conventional taxanes. One of said 14-hydroxy derivatives, referred to as IDN 5109, is at present under advanced clinical development. Said 14-hydroxylated derivatives can be easily prepared from natural 14-hydroxybaccatin.
It has now been found that IDN 5109 analogues bearing different substituents than the hydroxy group at the 14-position have surprising biological activity, as they are effective not only against taxane-resistant tumors but also against MDR cell lines.
The derivatives of the invention can be obtained by enolization of 13-ketobaccatin III and treatment with suitable electrophiles which can be converted into the desired group. Subsequent reduction of the C13 carbonyl and esterification with isoserine chains afford the compounds of the invention, as defined below.
7-Protected 13-ketobaccatin III is a very interesting compound as a key intermediate to 12,13-isotaxanes (Wicnienski et al., U.S. Pat. No. 5,821,363), to novel taxanes modified at the 13-position (Menichincheri et al., WO9614308) and at the C and D ring (Dubois et al., Tetrahedr. Lett. 2000, 41, 3331-3334; Uoto et al., Chem. Pharm. Bull. 1997, 45(12), 2093-2095). 7-Protected 13-ketobaccatin III is an important intermediate in the studies on total synthesis of taxol and analogues (Nicolaou et al., J. Am. Chem. Soc. 1995, 117, 624-633; Nicolaou et al. 1995, 117, 2409-2420; Nicolaou et al., U.S. Pat. No. 5,504,222). Some modifications of 7-protected 13-ketobaccatin III have also been reported, such as formation of hydrazones and oximes, (Menichincheri et al., WO9614308; Meninchincheri et al., Med. Chem. Res. (1996), 6(4), 264-292), direct treatment with oxidizing agents (Bombardelli et al., WO0212215; Harriman et al, Tetrahedr. Lett. 1995, 36(49), 8909-8912; or with reducing agents (Marder et al, Tetrahedr. 1995, 51(7), 1985-1994). Reactions of 13,14-enolization have not been described insofar, while rearrangement reactions in bases have been disclosed (Pinciroli et al., Tetrahedr. Lett. 1996, 37(52), 9365-9368; Yu and Liu, Tetrahedr. Lett. 1997, 38(23), 4133-4136).
According to a further aspect, the invention relates to a process for the 13,14 enolization of 13-ketobaccatin III to give intermediates sufficiently stable for further elaboration.